Rhinoviruses, which are members of the picornavirus family, trigger neutrophilic host inflammatory responses and are a major cause of asthma exacerbations. Rhinovirus-induced lower airway neutrophilic inflammation may initiate airway injury. However, neutrophils may also participate in the resolution of rhinovirus infections. The chemokine receptor CXCR2 and its ligands, e.g., interleukin-8, appear to be key factors in neutrophilic host responses to rhinovirus infection (Projects I and III). Rhinovirus research lacks a useful rodent model. There are no known rodent rhinoviruses, but mice are natural hosts for mengovirus, a picornavirus whose wild-type form causes systemic infections. In preliminary studies, inoculation of mice with attenuated mengoviruses (which were developed by Project V) via a respiratory route induced lower airway infection, neutrophilic inflammation, and expression of CXCR2 ligands, MCP-1 (monocyte chemoattractant protein-1; a CCR2 ligand that may indirectly regulate neutrophil function) (Project II), and interferon. These data closely mimic observations in human airways during rhinovirus-induced colds, demonstrating this model's relevance. The central hypotheses of this project are that replication-dependent release of CXCR2 ligands is critically important for picornavirus-induced lower airway neutrophilic inflammation and that, in the host response to lower airway picornavirus infection, low levels of neutrophil recruitment may be beneficial (i.e., enhance resolution of the viral infection), whereas high levels of neutrophil recruitment may be detrimental (i.e., mediate airway injury). To test these hypotheses: (1) Mechanisms mediating picornavirus-induced lower airway neutrophilic inflammation will be determined by inoculating mice with attenuated mengovirus, and determining the effects on outcomes of infection, including neutrophil recruitment, mucus production, and the production and cell source of CXCR2 ligands [KC, LIX (lipopolysaccharide-induced CXC chemokine), and MIP-2 (macrophage-inflammatory protein-2)]. (2) The role of neutrophils in mediating detrimental and/or beneficial host responses to lower airway infection with attenuated mengovirus will be determined by comparing neutrophil-depleted and control mice with regard to the outcomes of infection. (3) Using the comprehensive and unique set of reagents available for the study of murine immunology, the roles of CXCR2 and its ligands in mediating detrimental and/or beneficial neutrophil-dependent host responses to lower airway infection will be determined by comparing relevant knockout mice, mice treated with neutralizing anti-chemokine antibodies, and control mice with regard to the outcomes of infection. Relevance: Rhinovirus-induced colds are a major cause of asthma exacerbations. The absence of a rodent model of rhinovirus infection has hindered asthma research. By filling this gap, this unique mouse model should provide novel insights into human rhinovirus-induced airway inflammation and asthma exacerbations.